Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the U.S. with over 200,000 new cases in 2011 and estimated 5-year survival of only 15%. Although lung cancer was initially thought to be non-immunogenic, several lines of evidence now support harnessing the properties of the immune system to resist this cancer. Endogenous anti-tumor T cell responses delay malignant tumor progression in mouse models of lung adenocarcinoma (DuPage et al., 2011, Cancer Cell 19(1):72-85). Properties and distribution of infiltrating T cells has been linked to improved survival in NSCLC (Suzuki et al., 2011, Clin Cancer Res 17(16):5247-56; Ruffini et al., 2009, Ann Thorac Surg, 87(2):365-71). Recent studies with antibodies blocking negative regulators of T cell activation, termed T checkpoint blockade, have shown promising clinical activity in this tumor (Lynch et al., 2012, J Clin Oncol, 30(17):2046-54; Topalian et al., 2012, N Engl J Med, 366(26):2443-54). In particular, antibody mediated blockade of programmed death1 (PD1) recently led to objective tumor regression in 18% of patients with advanced NSCLC (Topalian et al., 2012, N Engl J Med, 366(26):2443-54).
Preclinical studies have shown that the anti-tumor effects of checkpoint blockade depend on underlying immunogenicity of tumors as well as the nature of target antigens. Immune mechanisms underlying responses to these agents may depend on the specific tumor type and the clinical setting such as prophylaxis or therapy (van Elsas et al., 2001, J Exp Med, 194(4):481-9). Although several antigenic targets have been identified in NSCLC, the nature of antigens that correlate with protective immunity in lung cancer remain unknown. Protective immunity may depend on targets critical for biology of the specific cancer. However, many of the antigens studied to date in lung cancer have not been shown to be critical for tumorigenicity.
SOX2 is a transcription factor shown to be critical for pluripotency and stemness in human embryonal stem cells and linked to their tumorigenicity (Takahashi et al., 2007, Cell, 131(5):861-72; Boyer et al., 2005, Cell, 122(6):947-56). Several studies have suggested an important role for SOX2 in the pathogenesis of lung cancer. SOX2 was identified as a common target of genomic amplification and a lineage survival oncogene in squamous cell cancers (Bass et al., 2009, Nat Genet, 41(11):1238-42; Hussenet & Manoir, 2010, Cell Cycle, 9(8):Epub; Yuan et al., 2010, PLoS One, 5(2):e9112; Lu et al., 2011, PLoS One, 5(6):e11022). Genomic abnormalities in SOX2 are also detected in preneoplastic lesions in the lung, implying it as a potential driver oncogene (McCaughan et al., 2010, Am J Respir Crit Care Med, 182(1):83-91). SOX2 has been implicated in the context of stem cells in lung tissue and cancer stem cells in adenocarcinoma of the lung (Kim et al., 2005, Cell, 121(6):823-35; Leung et al., 2011, PLoS One, 5(11):e14062; Tompkins et al., 2009, PLoS One, 4(12):e8248; Nakatsugawa et al., 2011, Lab Invest, 91(12):1796-804; Xiang et al., 2011, Br J Cancer, 104(9):1410-7). SOX2 was also shown to regulate oncogenic networks and tumorigenicity in diverse types of lung cancer (Chen et al., 2012, PLoS One, 7(5):e36326). While SOX2 and other pluripotency genes have not yet proven to be easily druggable, the capacity of the immune system to target these genes has been shown (Spisek et al., 2007, J Exp Med, 204(4):831-40; Dhodapkar et al., 2010, Proc Natl Acad Sci USA, 107(19):8718-23; Dhodapkar & Dhodapkar, 2011, Cancer J, 17(5):397-402; Dhodapkar, 2010, Curr Opin Immunol, 22(2):245-50).
Several studies have analyzed the presence of antibody responses to SOX2 in patients with lung cancer, and the presence of these antibodies has been particularly associated with small cell lung cancer (SCLC) (Gure et al., 2000, Proc Natl Acad Sci USA, 97(8):4198-203; Gnjatic et al., 2009, J Immunol Methods, 341(1-2):50-8; Titulaer et al., 2009, J Clin Oncol, 27(26):4260-7). It has been shown that the presence of naturally occurring T cell immunity to SOX2 was associated with improved survival and reduced risk of clinical malignancy in patients with monoclonal gammopathies (Spisek et al., 2007, J Exp Med, 204(4):831-40). However, the nature of T cell immunity to this antigen in lung cancer has not yet been described.
Thus, there is an unmet need in the art for biomarkers and assays for identifying patients more likely to benefit from immunotherapy for cancer. The present invention addresses this unmet need in the art.